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A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors

BACKGROUND: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. OBJECTIVE: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. PATIENTS AND METHODS: E...

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Autores principales: Bauer, Todd M., Moore, Kathleen N., Rader, Janet S., Simpkins, Fiona, Mita, Alain C., Beck, J. Thaddeus, Hart, Lowell, Chu, Quincy, Oza, Amit, Tinker, Anna V., Imedio, Esteban Rodrigo, Kumar, Sanjeev, Mugundu, Ganesh, Jenkins, Suzanne, Chmielecki, Juliann, Jones, Suzanne, Spigel, David, Fu, Siqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10345044/
https://www.ncbi.nlm.nih.gov/pubmed/37278879
http://dx.doi.org/10.1007/s11523-023-00965-7
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author Bauer, Todd M.
Moore, Kathleen N.
Rader, Janet S.
Simpkins, Fiona
Mita, Alain C.
Beck, J. Thaddeus
Hart, Lowell
Chu, Quincy
Oza, Amit
Tinker, Anna V.
Imedio, Esteban Rodrigo
Kumar, Sanjeev
Mugundu, Ganesh
Jenkins, Suzanne
Chmielecki, Juliann
Jones, Suzanne
Spigel, David
Fu, Siqing
author_facet Bauer, Todd M.
Moore, Kathleen N.
Rader, Janet S.
Simpkins, Fiona
Mita, Alain C.
Beck, J. Thaddeus
Hart, Lowell
Chu, Quincy
Oza, Amit
Tinker, Anna V.
Imedio, Esteban Rodrigo
Kumar, Sanjeev
Mugundu, Ganesh
Jenkins, Suzanne
Chmielecki, Juliann
Jones, Suzanne
Spigel, David
Fu, Siqing
author_sort Bauer, Todd M.
collection PubMed
description BACKGROUND: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. OBJECTIVE: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. PATIENTS AND METHODS: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1–3 and 8–10 of a 21-day treatment cycle. RESULTS: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified). CONCLUSION: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02482311; registered June 2015. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11523-023-00965-7.
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spelling pubmed-103450442023-07-15 A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors Bauer, Todd M. Moore, Kathleen N. Rader, Janet S. Simpkins, Fiona Mita, Alain C. Beck, J. Thaddeus Hart, Lowell Chu, Quincy Oza, Amit Tinker, Anna V. Imedio, Esteban Rodrigo Kumar, Sanjeev Mugundu, Ganesh Jenkins, Suzanne Chmielecki, Juliann Jones, Suzanne Spigel, David Fu, Siqing Target Oncol Original Research Article BACKGROUND: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. OBJECTIVE: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. PATIENTS AND METHODS: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1–3 and 8–10 of a 21-day treatment cycle. RESULTS: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified). CONCLUSION: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02482311; registered June 2015. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11523-023-00965-7. Springer International Publishing 2023-06-06 2023 /pmc/articles/PMC10345044/ /pubmed/37278879 http://dx.doi.org/10.1007/s11523-023-00965-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Bauer, Todd M.
Moore, Kathleen N.
Rader, Janet S.
Simpkins, Fiona
Mita, Alain C.
Beck, J. Thaddeus
Hart, Lowell
Chu, Quincy
Oza, Amit
Tinker, Anna V.
Imedio, Esteban Rodrigo
Kumar, Sanjeev
Mugundu, Ganesh
Jenkins, Suzanne
Chmielecki, Juliann
Jones, Suzanne
Spigel, David
Fu, Siqing
A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
title A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
title_full A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
title_fullStr A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
title_full_unstemmed A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
title_short A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors
title_sort phase ib study assessing the safety, tolerability, and efficacy of the first-in-class wee1 inhibitor adavosertib (azd1775) as monotherapy in patients with advanced solid tumors
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10345044/
https://www.ncbi.nlm.nih.gov/pubmed/37278879
http://dx.doi.org/10.1007/s11523-023-00965-7
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